Dr. Torday László, MD PhD Assistant professor

University of Szeged

Department of Oncotherapy

Oncological treatment of renal cell

carcinoma

Locations of RCC

Risk factors

Smoking

Obesity

Hypertension

Long term dialysis

Chemical substances: trichlor-acetylen, asbest, cadmium

Occupational risk: leather and shoe industry, iron and steel industry, car sales and gas stations

Drinking pilsen type beer?

Genetical abnormalities as reasons of

RCC

Von Hippel-Lindau (VHL) syndrome

– Rare genetic disease, mutation of the VHL gene

– In 50% of affected patients will develop RCC

Hereditary papillary RCC (HPRC)

– MET-kinase genetic mutations: papillary RCC of both sides

Birt-Hogg-Dubé syndrome

– Rare

Three classical signs

Hematuria

– 60%

Abdominal pain

– 40%

Palpable resistency in the stomach

T Stages

TX Primary tumor cannot be assessed.

T0 No evidence of primary tumor.

T1 Tumor ≤7 cm in greatest dimension, limited to the kidney.

T1a Tumor ≤4 cm in greatest dimension, limited to the kidney.

T1b Tumor >4 cm but not >7 cm in greatest dimension, limited to the kidney.

T2 Tumor >7 cm in greatest dimension, limited to the kidney.

T2a Tumor >7 cm but ≤10 cm in greatest dimension, limited to the kidney.

T2b Tumor >10 cm, limited to the kidney.

T3 Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia.

T3a Tumor grossly extends into the renal vein or its segmental (muscle containing) branches, or tumor invades perirenal and/or renal sinus fat but not beyond Gerota fascia.

T3b Tumor grossly extends into the vena cava below the diaphragm.

T3c Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava.

T4 Tumor invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland).

Staging

NX Regional lymph nodes cannot be assessed.

N0 No regional lymph node metastasis.

N1 Metastases in regional lymph node(s).

M0 No distant metastasis.

M1 Distant metastasis.

Stage T N M

I T1 N0 M0

II T2 N0 M0

III T1 or T2 N1 M0

T3 N0 or N1 M0

IV T4 Any N M0

Any T Any N M1

Treatment of Stage I disease

Radical nephrectomy

Simple nephrectomy

Partial nephrectomy (selected patients)

EBRT (palliative)

Arterial embolization (palliative)

Clinical trials.

Treatment of Stage II disease

Radical nephrectomy

Nephrectomy before or after EBRT (selected patients)

Partial nephrectomy (selected patients)

EBRT (palliative)

Arterial embolization (palliative).

Clinical trials.

Treatment of Stage III disease

Radical nephrectomy with renal vein and, as necessary, vena caval resection (for T3b tumors). Radical nephrectomy with lymph node dissection.

Preoperative embolization and radical nephrectomy

EBRT (palliative)

Tumor embolization (palliative)

Palliative nephrectomy.

Preoperative or postoperative EBRT and radical nephrectomy

Clinical trials involving adjuvant interferon-alpha.

Treatment of Stage IV disease

Radical nephrectomy (for T4, M0 lesions).

Cytoreductive nephrectomy

Temsirolimus.

Sunitinib

Pazopanib

Bevacizumab with or without interferon-alpha

Everolimus (for patients who have previously been treated with sunitinib and/or sorafenib)

Sorafenib

Interferon-alpha

IL-2

Palliative EBRT.

Histological subtypes of renal cell

cancer (RCC)

Kidney cancers : 3% of solid tumors

US data: new cases: 64,770, deaths: 13,570

80-85%: renal cell cancer, from this 75% clear cell

Jermann M et al. Cancer Chemother Pharmacol. 2006;57:533-539; Linehan WM et al. J Urol. 2003;170:2163-2172; Motzer RJ et al. N Engl J Med. 1996;335:856-875.

Ttype Clear cell Papillary type 1 Papillary type 12 Chromophob Oncocytoma

75% 5% 10% 5% 5%

Ggene VHL Met FH BHD

Renal Clear Cell Carcinoma (RCC)

RCC: most of the kidney cancers – 33% of patients eare metastatic in the time of

diagnosis1

– Less than 10% of mRCC patients live longer than

5 years2

Limited OS benefit from traditional

treatments

– mRCC: usually chemoresistant3

– Few patients benefitting from cytokines4

1. Lam et al. World J Urol 2005;23:202, 2. National Cancer Institute. SEER Cancer Statistics. Available at: http://seer.cancer.gov/statistics , 3. Lilleby et al. World J Urol 2005;23:175, 4. NCCN Clinical Practice Guidelines in Oncology.

Kidney Cancer. V2 2009

Historical treatment

Medián OS: 13 hónap N = 463 pts

Motzer RJ, et al. J Clin Oncol. 2002;20:289-296.

OS

(%

)

Arm A: MPA (123)

Arm B: IFN (122)

Arm C: IL-2 (125)

Arm D: IFN + IL-2 (122)

0

20

40

60

80

0 6 12 18 24 30 36 42 48

100

Time from randomization (months)

Median OS

Arm A: 14.9 month (95% CI: 11.7–19.2)

Arm B: 15.2 month (95% CI: 12.8–19.9)

Arm C: 15.3 month (95% CI: 13.3–20.0)

Arm D: 16.8 month (95% CI: 14.0–18.9)

The PERCY QUATTRO Study:

the end of immunotherapy

“Pharmacoptosis”:

Progreammed death of IFN and IL-2

…tried my very best…

P. Schöffski

…tried my very best…

The 1971 hypothesis of Folkman

Theoretical bases of therapy

Folkman J. N Engl J Med 1971;285:1182–6

‘Without vascularisation solid tumors remain in a dormant stage and their

size not more than 2–3mm3; this is the size

which is determined by the intratumorous

diffusional capacity of oxygen and nutrients”

The tumor and its environment

induces VEGF expression

EGF

IGF-1 PDGF

IL-8

bFGF

Hypoxia

COX-2

NO

Oncogenes

VEGF release Binding to VEGF receptor

Activation of VEGF receptor

H2O2

Proliferation Survival Migration

ANGIOGENESIS Permeability

Overexpression

(MMP, tPA, uPA, uPAr,

eNOS, etc.)

– P

– P

P–

P–

IGF = insulin-like growth factor; PDGF = platelet-derived growth factor

VEGF: vascular endothelial

growth factoe

Angiogenic schwitch

Bergers G, et al. Nature 2002;3:401–10

Small tumor (1–2mm)

• Avascular

• Hided

Bigger tumor

• Vascularised

• Metasztatic

potential

Angiogenic „switch”

Overexpression of elements of

Signal transduction (pl. VEGF)

Role of angiogenesis in tumor formation,

growth and metastasis

Poon RT-P, et al. J Clin Oncol 2001;19:1207–25

Stages of tumorous progression: role of angiogenesis

Premalignant stage

Malignant tumor

Tumor growth

Vascular invasion

Dormant mikro- metastasis

„Living” metastasis

Avascular tumor

Angiogenic switch

Vascularised tumor

Tumor cell invasion

Metastasis to distant organs

Secondary angiogenezis

Effect of anti-VEGF treatment on

tumor vasculature

Baluk, et al. Curr Opin Genet Dev 2005; Inai, et al. Am J Pathol 2004; Erber, et al. FASEB J 2004

Tong, et al. Cancer Res 2004; Jain. Nat Med 2001; Jain. Science 2005; Lee, et al. Cancer Res 2000

Willett, et al. Nat Med 2004; Gerber, et al. Cancer Res 2005; Warren, et al. J Clin Invest 1995

Early effecgt Long term effect

Normalisation of remaining

tumorous microvasculature

1

2

Decrease of tumorous

microvasculature Decrease of new

tumorous

microvasculature

3

Scientific facts

The RCC is a hypervascularised tumor-3

–Angiogenesisi is needed fro tumorous growth

over1-2 mm3

Inactivated VHL tumor supresor gene1-3

–Overproduction of „hypoxia inducible factor”

(HIF), transcription of HIF

target genes

–„Vascular endothelial growth

factor” (VEGF)

–„Transforming growth

factor” (TGF)-α

–„Platelet-derived

growth factor” (PDGF)

RCC=renal cell carcinoma; mm=millimeter; VHL=von Hippel-Lindau; VEGFR-TKI=vascular endothelial growth factor receptor-tyrosine kinase.

Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000; Decker HJH et al. Cancer Genetics Cytogenet. 1997;93:74-83; Costa LJ, Drabkin HA. Oncologist. 2007;12:1404-1415.

22

HIF-1α

HIF-1α

Ubiquitination and degradation

HIF-1β Mutáns pVHL

X

Angiogenesis

The VHL protein not binds to HIF-1α, which avoyds proteolysis

Increased

transcription

X

Well differentiated RCC, low VEGF-expression: good prognosis

Poorly differentiatedRCC, high VEGF-expression: poor prognosis

Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000. 23

Firts line treatment: scientific

considerations

Strategies of anti-angiogenesis1-3

– Anti-VEGF antibody (bevacizumab)

– VEGFR-TKI (sunitinib)

– „Mammalian target of rapamycin” (mTOR) inhibitor (temsirolimus)

– Cytokine therapy

RCC=renal cell carcinoma; mm=millimeter; VHL=von Hippel-Lindau; VEGFR-TKI=vascular endothelial growth factor receptor-tyrosine kinase.

1. Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000; 2. Decker HJH et al. Cancer Genetics Cytogenet. 1997;93:74-83; 3. Costa LJ, Drabkin HA. Oncologist. 2007;12:1404-1415.

MSKCC risk factors

KPS = Karnofsky PS; LDH = lactate dehydrogenase; LLN = lower limit of normal; MSKCC = Memorial Sloan-Kettering Cancer Center; ULN = upper limit of normal.

1. Motzer RJ, et al. J Clin Oncol. 2002;20:289-296; Motzer RJ, et al. J Clin Oncol. 2004;22:454-463

MSKCC Criteria 20021

KPS <80

Time from

dignosis to

treatment

<12 hónap

Hemoglobin <LLN

LDH >1.5 x ULN

Corrected serum

calcium >10.0 mg/dL

0 risk factor = favorable prognosis

1 or 2 risk factor = intermediate

prognosis

≥3 risk factor = ppoor prognosis

Prognosis of mRCC: MSKCC risk

model (cytokin éra)

favorable : 19.9 months (n = 164)

intermediate: 10.3 months (n = 348)

poor: 3.9 months (n = 144)

Time from the start of systemic treatment

OS

, %

100

80

60

40

20

0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Motzer RJ, et al. J Clin Oncol. 1999;17:2530–2540.

Median OS

mRCC prognosis: risk factor model:

TKI era

1.0

0.8

0.6

0.4

0.2

0.0 0 10 20 30 40 50

good: 0 factor (OS NR months)

intermediate: 1–2 factor (OS 27 months)

poor: 3–6 factor (OS 8.8 months)

Months from the start of the treatment

pro

babili

ty

p<0.0001

Heng DYC, et al. J Clin Oncol. 2009; 27:5794–5799.

OS

*Prognostic factors : Time from diagnosis to treatment <1 év, KPS <80%, low hemoglobin, High corrected calcium, high neutrophil count , high platelet count

Mechanism of action: bevacizumab

Molecular target

– Monoclonal

antibody against

VEGF

Effects

– Block the

binfding of VEGF

to its own

receptor

– Decrease the

proliferation of

endothelial cells

– Decrease the

VEGFR-induced

proliferation of

endothelial cells

Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.

Bevacizumab: Phase III studies in

mRCC

Patient population: mRCC, no previous tretament

CALGB 90206

N = 732

BO17705 (AVOREN)

N = 649

IFN- 9.0 MU TIW

FN- 9.0 MU TIW + Bevacizumab

10 mg/kg d1,15

Randomised Randomised

IFN-α 9.0 MU TIW + Bevacizumab

10 mg/kg d1,15

IFN-α 9.0 MU TIW + Placebo

CALGB 902061 AVOREN2

Terápia IFN- IFN- + Bev IFN- + Bev IFN- + placebo

ORR 13.1% 25.5% 31% 12%

PFS (median) 4.9 months 8.4 months 10.4 months 5.5 months

1. Rini B, et al. J Clin Oncol. 2009;27(Suppl 15s) (Abstract LBA5019). 2. Escudier B, et al. J Clin Oncol. 2009;27(Suppl 15s):5020 (Abstract).

0 6 12 18 24

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Patient number

Bevacizumab + IFN 327 196 107 18 0

IFN + placebo 322 137 59 15 0

AVOREN: PFS P

rob

ab

ilit

y o

f p

rog

ress

ion

Time (months)

Bevacizumab + IFN

IFN + placebo

5.4 10.2

Escudier B, et al. Lancet 2007;370:2103–11.

HR=0.63; p<0.0001

Mechanism of action: sunitinib

Molekular targets

– TKI

– VEGFR, PDGFR,

KIT, FLT3, CSF-1R,

RET

Effects

– Blocks the signal

transduction of

target molecules

– Decrease

vascularisation and

endothelial

proliferation

Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.

1st line sunitinib vs. IFN-α:

Phase 3 trial design

101 australian, brasilian, canadian, european and USA center

N = 750

n = 375

n = 375

Sunitinib

50 mg/day, per os

4 weeks on, 2 weeks off

IFN-α

3 MU sc. TIW week 1,

6 MU sc. TIW week 2

9 MU sc. TIW after week 3

Inclusion criteria

• Older than 18 years

• mRCC

• Clear cell histology

• No previous systemic treatment

• Measurable disease by RECIST

• ECOG PS 0 or 1

• Adequate organ functions

RANDOMISATION

Motzer RJ, et al. N Engl J Med 2007;356:115–124.

RECIST = response evaluation criteria in solid tumors; SC = subcutaneously; TIW = three times weekly.

Primary endpoint: PFS

Sunitinib vs. IFN-α: efficacy data

Best tumor response

Sunitinib (n=375) IFN- (n=375)

Response N % N %

ORR 176 47 46 12

CR 11 3 4 1

PR 165 44 42 11

SD 150 40 202 54

PD 26 7 69 18

Motzer RJ, et al. J Clin Oncol 2009;27:3584–90.

Sunitinib vs. IFN-α: PFS

No. at Risk

Sunitinib: 375 240 156 54 10 1

IFN-α: 375 124 46 15 4 0

Motzer RJ, et al. N Engl J Med. 2007;356:115-124; Motzer RJ, et al. J Clin Oncol. 2007;20(Suppl 18s):5024 (Abstract).

HR = 0.538 95% CI (0.439, 0.658)

P<0.00001

0 5 10 15 20 25 30

Time, months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ilit

y o

f P

FS

Sunitinib,

Median: 11.0 months,

95% CI:10.7–13.4)

IFN-

Median: 5.1 months

(95% CI:3.9–5.6)

HR = hazard ratio.

Primary endpoint

Sunitinib vs. IFN-α: OS

Total deaths

Sunitinib: 190

IFN-: 200

0 3 6 9 12 15 18 21 24 27 30 33 36

Time, months

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

ba

bil

ity o

f O

S (

%)

HR = 0.821 (95% CI: 0.673–1.001)

P=0.051 (logrank)

0 / 375 44 / 326 38 / 283 48 / 229 42 / 180 14 / 61 4 / 2

nDeath/nRisk Sunitinib

0 / 375 61 / 295 46 / 242 52 / 187 25 / 149 15 / 53 1 / 1

nDeath/nRisk IFN-

Sunitinib (n = 375)

Median: 26.4 months

(95% CI: 23.0–32.9)

IFN- (n = 375)

Median: 21.8 months

(95% CI:17.9–26.9)

Motzer RJ, et al. J Clin Oncol. 2009;27:3584-3590.

Sunitinib vs. IFN-α: OS of patients not

receiving post-study treatment

*Includes 20 patients who crossed over to sunitinib on study.

Figlin RA, et al. J Clin Oncol. 2008;26 (May 20 suppl) [Abstract 5024].

HR = 0.647

(95% CI: 0.483–0.870)

P=0.0033 (logrank)

0 3 6 9 12 15 18 21 24 27 30 33 36

Time, months

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

ba

bil

ity o

f O

S

Sunitinib (n = 193)

Median: 28.1 months

(95% CI:19.5–NA)

IFN- (n = 162)

Median: 14.1 months

(95% CI:9.7–21.1)

Pazopanib vs. placebo in the first and

second line treatment of mRCC

Inclusion criteria

• Locally advanced or mRCC

• Primarily clear cell histology

• Measurable disease (≥1 lesion)

• 1 previous systemic treatment (cytokine based)*

R

A

N

D

O

M

I

Z

A

T

I

O

N

2:1

Primary endpoint: PFS

No OS data available yet

Pazopanib 800 mg/day

Placebo N = 400

• Open-label extension study (Pazopanib 800 mg; N = 71)

*Patients with no prior treatment were also permitted to enroll in the study

Sternberg C, et al. J Clin Oncol. 2010 ;28:1061–1068.

Pazopanib* vs Placebo: tumor

response: independent review

Independent review

Pazopanib* (n=290)

Placebo (n=145)

No. of patients (%) CR 1 (<1) 0 (0) PR 87 (30) 5 (3)

SD 110 (38) 59 (41)

PD 51 (18) 58 (40)

ORR (CR + PR) 88† (30) 5 (3)

†P < .001, based on Fischer’s exact test comparison of treatment arms.

CR=complete response; PR=partial response.

Sternberg CN, et al. J Clin Oncol. 2010;28:1061-1068.

Pazopanib vs. placebo: PFS

Patients not receiving prior therapy Every ITT patient

Sternberg C, et al. J Clin Oncol. 2010 ;28:1061–1068.

Mechanism of action: sorafenib

Molecular targets – TKI

– Like sunitinib —

VEGFR, PDGFR, RAF,

KIT, FLT3

Effects – Inhibits downstream

signal transduction

– Decreases

vascularisation and

endothelial cell

proliferation

Rini BI, Atkins MB. Lancet Oncol. 2009;10:992-1000.

Sorafenib vs. IFN-α in first line:

Phase II

Escudier B, et al. J Clin Oncol. 2009;27:1280–1289.

Sorafenib

600 mg BID

(n = 44)

Sorafenib

400 mg BID

(n = 50)

Inclusion criteria:

Clear cell histology

No prior systemic therapy

ECOG PS 0 or 1

Every MSKCC prognostic groups

Randomisation:1:1

N = 189

Stratification: MSKCC prognostic categories

Pro

gre

ss

ion

Sorafenib

400 mg BID

(n = 97)

IFN-α

9 MU TIW

(n = 92)

1. period 2. period

BID = twice daily

Sorafenib vs. IFN: Median PFS P

rog

ressio

n-f

ree S

urv

ival (%

pati

en

ts)

100

80

60

40

20

00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Time From Randomization (months)

Median PFS (121 events/189 patients)

Sorafenib = 5.7 months

IFN = 5.6 months

Hazard Ratio=0.883

p=0.504 (log-rank test)

Escudier B, et al. J Clin Oncol. 2009;27:1280–1289.

The PI3K/AKT/mTOR signal transduction

pathway in the tumor: aberrant activation mTOR activity ofter

increased in cancer

cells :

– Increased EGFR, IGF-1R,

és VEGFR signal

transduction1,2

– Appearance of function

modifying mutationse.g.

In PI3K, Ras/Raf, erbB

receptors, and Abl2-4

– Loss of function of

negative regulators (e.g.

PTEN és TSC1/2)3

1. Harris TE, et al. Sci STKE. 2003;(212):re15; 2. Humar A, et al. FASEB J. 2002;16:771-780; 3. Huang S, et al. Cancer Biol Ther. 2003;2:222-232; 4. Edinger and Thompson. Mol Biol Cell. 2002;13:2276-2288.

Temsirolimus phase III study on RCC

patients with poor prognosis

Inclusion criteria

• Locally advanced or mRCC

• Primarily clear cell histology

• 3/6 poor risk sign

• LDH >1.5 x ULN

• Hgb < LLN

• Corrected Ca++ >10

• KPS <70

• DFI <1 year

• Multiple organ metasteses)

RANDOMISATION

Primary andpoint: OS

TEM 25 mg QW

(n = 209)

IFN 6 MU + TEM 15 mg QW (n = 210)

N = 626

IFN 3 MU-18 MU

(n = 207)

*Modified MSKCC poor risk; †Stratification by country and nephrectomy status.

DFI = disease-free interval.

Hudes G et al. N Engl J Med. 2007;356:2271–2281.

*Modified MSKCC poor risk; †Stratification by country and nephrectomy status.

Temsirolimus vs. IFN: OS

Parameter

IFN

Arm 1

(n=207)

TEMSR

Arm 2

(n=209)

TEMSR + IFN

Arm 3

(n=210)

Median survival (mos) 7.3 10.9 8.4

Comparisons Arm 2:Arm 1 Arm 3:Arm 1

Stratified log-rank p 0.0069 0.6912

Parameter

IFN

Arm 1

(n=207)

TEMSR

Arm 2

(n=209)

TEMSR + IFN

Arm 3

(n=210)

Median survival (mos) 7.3 10.9 8.4

Comparisons Arm 2:Arm 1 Arm 3:Arm 1

Stratified log-rank p 0.0069 0.6912

1.0

0.8

0.6

0.4

0.2

0

Sur

viva

l dis

trib

utio

n fu

nctio

n

0 5 10 15 20 25 30 35Time to death

Arm 3: IFN + Temsirolimus

Arm 2: TemsirolimusArm 1: IFN

Hudes G et al. N Engl J Med. 2007;356:2271–2281.

Toxicity profiles of drugs used in first

line (Grade 3/4) Sunitinib1,2 Bev + IFN-α3 Sorafenib4 Pazopanib5 Temsirolimus6

AE (%)

Phase III

1st line

Phase III

1st line

Phase II

1st line

Phase III

1st line

Phase III*

1st line

Anorexia – 3 0 2 3

Asthenia 4 10 – 3 11

Diarrhea 5 2 6 4 1

Dyspnea – <1 0 – 9

Fatigue 7 12 5 2 –

Hand-foot szindróma 5 – 11 – –

Hyperglycemia 5 – – <1 11

Hypertension 8 3 2 4 –

Anemia 4 3 – – 20

Neutropenia 12 4 – 2 3

Thrombocytopenia 8 2 – 2 1

Leukopenia 5 – – 0 1

Tretament interruption due to

AE

19 28 11 16 7

*Poor prognostic patients based on MSKCC criteria (+ metasztatically involved organs)

1. Motzer RJ, et al. N Engl J Med. 2007;356:115–124. 2. Figlin RA, et al. J Clin Oncol. 2008;26(Suppl. 15S):5024 (Abstract). 3. Escudier B, et al. J Clin Oncol. 2009;27:1280–1289. 4. Escudier B, et al. Lancet. 2007;370:2103–2111. 5. Sternberg C, et al. J Clin Oncol. 2010 ;28:1061-1068. 6. Hudes G, et al. N Engl J Med. 2007;356:2271−2281.

Hand-foot skin reaction

Relapse or metastatic disease or irresectable

Clear cell histology

Level 1 evidence*

– Sunitinib

– Bevacizumab + IFN-α

– Pazopanib

– Temsirolimus (for patients with poor prognosis)

NCCN Guidelines: 1st line treatment

* Level 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus.

† Poor prognosis patients, defined as those with ≥3 predictors of short survival.

NCCN = National Comprehensive Cancer Network; RT = radiation therapy.

Kidney Cancer, NCCN v.2.2010 Clinical Practice Guidelines in Oncology. Available at www.NCCN.org.

Everolimus: Post-TKI Therapy (RECORD-1)

RCC=renal cell carcinoma; RECIST=Response Evaluation Criteria in Solid Tumors; PS=performance status; VEGFR-TKI=vascular endothelial growth factor receptor tyrosine kinase inhibitors; MSKCC=Memorial Sloan-Kettering Cancer Center; qd=every day; BSC=best supportive care. IFN-α=interferon alfa.

1. Motzer RJ, et al, for the RECORD-1 Study Group. Lancet. 2008;372:449-456; 2. Motzer RJ, et al, for the RECORD-1 Study Group. Cancer. 2010 ;116(18):4256-4265.

Inclusion criteria

Metastatic clear cell RCC

Progression on sunitinib, or sorafenib, or 6 months after finishing sunitinib/sorafenib treatment

Measurable disease (RECIST)

Karnofsky PS ≥70%

Adequate bone marrow, liver and kidney function

Stratification

Prior VEGFR-TKI: 1 vs 2

MSKCC risk: good, intermediate, poor

R A

N D

O M

I ZA

TIO

N Everolimus 10 mg qd + BSC

(n=277)

Placebo + BSC (n=139)

Cross over to everolimus in

case of progression

2:1

Primary endpoint Progression free survival (PFS)

Secondary endpoints Objective response rate(ORR), Overall survival (OS), Toxicity (AE-s), Quality of life (QoL)

RECORD-1: PFS

PFS improved in every MSKCC risk groups, independently from the type of previous VEGFR-TKI therapy

100

80

60

40

20

0

0 2 4 6 8 10 14

Pro

bab

ilit

y,

%

Everolimus (median PFS: 4.90 months) Placebo (median PFS: 1.87 months)

Hazard Ratio = 0.33

95% CI: 0.25, 0.43

Log-Rank P Value <0.001

Time, months 12

PFS=progression-free survival

Reprinted from Motzer RJ, et al, for the RECORD-1 Study Group. Cancer. 2010;116(18):4256-4265.

0

Time, months

30

40

50

60

70

80

90

100

Pro

bab

ilit

y, %

Everolimus (n=277; Kaplan-Meier Median: 14.8 hó)

Placebo (n=139; Kaplan-Meier Median: 14.4 hó)

20 2 4 6 8 10 12 14 16 18 22

Motzer RJ, et al, for the RECORD-1 Study Group. Cancer. 2010;116(18):4256-4265.

RECORD-1 OS

The real evaluation of OS is biased by the cross-over of 81% of placebo treated patients to everolimus arm after progression

Sorafenib

400 mg bid ORR 10%

SD 74%

PFS 5.5 months

Priary endpoint

• PFS (P=0.01)

• OS (P=0.04)

Secondary

endpoint

• ORR

TARGET: Phase III, sorafenib vs.

placebo, 2nd line

Placebo* ORR 2%

SD 53%

PFS 2.8 months

1:1

randomisation

n~905

Inclusion criteria

• Histologically confirmed

non-resectable or

metastatic disease

• Clear cell histology

• Measurable disease

• Failure of at least one prior

therapy

• ECOG PS 0 or 1

• Good organ functions

• No brain metastasis

• Poor prognostic group

excluded

Stratification

MSKCC criteria

Country

*Crossover initiated 6/05.

Escudier B, et al. N Engl J Med. 2007;356:125–134; Bukowski R, et al. Am J Clin Oncol. 2007;30:220–227.

OS Sorafenib Placebo

Final analysis 17.8 hó 15.2 hó

Censored analysis 17.8 hó 14.3 hó

TARGET: OS analysis TARGET: 561 death

OS analysis defined by protocol TARGET: pre-planned secondary analysis†:

data of censored sorafenib receiving patients excluded

0 4 8 12 16 20 24 28 32 36 40

Months after randomisation

Pro

po

rtio

n o

f th

e liv

ing

pati

en

ts 1.00

0.75

0.50

0.25

0.00

● 216/452 patient receiving placebo changed to sorefenib

● 61% of patients of placebo arm has received sorefenib

Sorafenib

Placebo

HR = 0.88*

95% CI: 0.74–1.04

*Non-significant (P=0.146); †Planned analysis prior to unblinding of the OS data; O’Brien-Fleming threshold for statistical significance =0.037.

0 4 8 12 16 20 24 28 32 36 40

Months after randomisation

Pro

po

rtio

n o

f th

e liv

ing

pa

tie

nts

1.00

0.75

0.50

0.25

0.00

HR = 0.78*

95% CI: 0.62–0.97

P=0.0287*

Sorafenib (N = 451)

Placebo (N = 452)

Escudier B, et al. N Engl J Med. 2007;356:125–134. Bukowski R, et al. Am J Clin Oncol. 2007;30:220–227.

Pazopanib vs. placebo: 2nd line

Inclusion criteria

• Locally advanced or mRCC

• Primarily clear cell histology

• Measurable disease (≥1 lesion)

• 1 prior systemic treatment (cytokine based)*

R

A

N

D

O

M

I

Z

A

T

I

O

N

2:1

Primary endpoint: PFS

Pazopanib 800 mg/day

Placebo N = 400

• Open-label extension study (Pazopanib 800 mg; N = 71)

*Patients with no prior treatment were also permitted to enroll in the study

Sternberg C, et al. J Clin Oncol. 2010 ;28:1061–1068.

Pazopanib PFS on cytokine pretreated

patients HR = 0.54

95% CI (0.35, 0.84)

P value <0.001

Median PFS

Pazopanib: 7.4 hónap

Placebo: 4.2 hónap

1.0

0.8

0.6

0.4

0.2

0.0 0 5 10 15 20

Months

Pro

po

rtio

n p

rog

ress

ion

fre

e

Patients receiving treatment

Pazopanib 135 75 37 18 5

Placebo 67 16 7 Sternberg C, et al. J Clin Oncol. 2009;27(Suppl 15s):5021 (Abstract).

Less potent

More potent

Pote

ncy: IC

50 (

nM

)

Figure modified using data from Chow LQM, Eckhardt SG. J Clin Oncol. 2007 Eskens FALM, et al. AACR 2008. Abstract LB-201; Hu-Lowe DD, Clin Cancer Res 2008

VEGFR-1

VEGFR-2

VEGFR-3

Motesanib AMG-706

Sunitinib ABT-869 *Pazopanib Sorafenib Vatalanib PTK787

Vandetanib Cediranib Axitinib Tivozanib AV-951

1,000

100

10

1

0.1

0.01

Relative potencies of VEGF TKI-s

AXIS: Fázis III, axitinib vs. sorafenib,

2nd line

Primary endpoint: PFS

Secondary endpoint: OS, ORR

Axitinib 5 mg BID

Sorafenib 400 mg BID

Inclusion criteria

mRCC with clear cell histology

Failure of one prior treatment:

Sunitinib

Bevacizumab + IFN-α

Temsirolimus

Or cytokin

Stratification: Prior treatment, ECOG PS

N=717

Rini B, et al. ASCO 2011

R

A

N

D

O

M

I

S

A

T

I

O

N

AXIS: Az axitinib szignifikánsan

megnyújtja a PFS-t

361 256 202 145 96 64 38 20 10 1 0

362 224 157 100 51 28 12 6 3 1 0

Betegszám

Axitinib

Sorafenib

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Idő (hónap)

P<0.0001 (log-rank)

Stratified HR 0.665

(95% CI :0.544–0.812)

0 2 4 6 8 10 12 14 16 18 20

Axitinib

Sorafenib

mPFS, hónap 95% CI

6.7 4.7

6.3–8.6 4.6–5.6

Pro

gre

sszió

me

nte

s tú

lélé

s

Rini B, et al. ASCO 2011

PFS and prior treatments

Prior treatment

Axitinib

(n=361)

Sorafenib

(n=362) HR P value*

Cytokines (n=251)

IRC

Investigator

12.1

12.0

6.5

8.3

0.464

0.636

<0.0001

0.005

Sunitinib (n=389)

IRC

Investigator

4.8

6.5

3.4

4.5

0.741

0.636

0.011

0.0002

Temsirolimus (n=24)

IRC

Investigator

10.1

2.6

5.3

5.7

0.511

1.210

0.142

0.634

Bevacizumab (n=59)

IRC

Investigator

4.2

6.5

4.7

4.5

1.147

0.753

0.637

0.213

*One-sided log-rank test stratified by ECOG PS Rini B, et al. ASCO 2011

The ORR of axitinib is better

Best tumor response, % Axitinib Sorafenib

Partial response*

Stable disease

Progressive disease

Not defined

19.4

49.9

21.6

6.1

9.4

54.4

21.0

11.6

Risk ratio (95% CI) 2.1 (1.4–3.0)

*Axitinib vs. sorafenib: P = 0.0001

Rini B, et al. ASCO 2011

Results of treatment of cytokin

refrakter mRCC

Study

n

ORR (%)

Median

PFS/TTP (mos)

Median

OS (mos)

Sorafenib (vs. placebo)1 903 10 vs. 2 5.5 vs. 2.8 17.8 vs. 15.2

Pazopanib (vs. placebo)4 202 29 vs. 3 7.4 vs. 4.2 NA

Sunitinib2 106 34 8.3 23.94

Sunitinib3 63 40 8.7 16.4

Axitinib5 52 44 15.7 29.9

1. Escudier B, et al. N Engl J Med. 2007;356:125–134. 2. Motzer RJ, et al. J Urol. 2007;178:1883-1887. 3. Motzer RJ, et al. J Clin Oncol. 2006;24:16–24. 4. Sternberg C, et al. J Clin Oncol. 2009;27(Suppl 15s):5021 (Abstract). 5. Rixe O, et al. Lancet Oncol. 2007;8:975–984.

* Date presented are not from comparative trials!

NCCN Guidelines: 2nd line treatments

Clear cell histology

• Clinical study

• Sunitinib (1* after cytokine treatment, 2A† after other TKI treatment)

• Sorafenib (1 after cytokine treatment, 2A after other TKI treatment)

• Pazopanib (1 after cytokine treatment, 3§ after other TKI treatment)

• Everolimus (1 after TKI treatment)

Level 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus.

† Level 2A: Uniform NCCN consensus based on lower-level evidence, including clinical experience, that the recommendation is appropriate.

§ Level 3: Recommendation is based on any level of evidence but reflects major disagreement.

Kidney Cancer, NCCN v.2.2010 Clinical Practice Guidelines in Oncology. Available at www.NCCN.org.

Europen mRCC treatment

landscape

Patient group Treatment Option

No prior treatment

MSKCC: good

or intermediate

Sunitinib Bevacizumab

+ IFNα Pazopanib

HD IL-2

MSKCC: poor

Temsirolimus Sunitinib

Second-line patient

Cytokine

refracter

Sorafenib Pazopanib Sunitinib

VEGF/VEGFR

TKI refracter Everolimus

Sequential TKI or VEGF

inhibitor

Treatment of mRCC in Hungary

AVOREN ASCO 2009

Figlin ASCO 2008

Multiple studies

Hudes 2007

Gore ASCO 2008

Kane 2006

5.3

Improving PFS in the 1st line treatment

of mRCC

Time (months)

Best supportive care

INF-α+ IL-2+5-FU

Temsirolimus

Sunitinib

Bevacizumab + INF-α

Sorafenib

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

11.0

5.5

5.7

2–3

10.4

Nexavar PI

Kane et al. Clin Cancer Res. 2006;12:7271; Gore et al. ASCO 2008; Hudes et al. N Engl J Med 2007;356:2271; Nexavar PI; Rini et al. ASCO 2009; Escudier et al. ASCO 2009; Figlin et al. ASCO 2008; Sternberg et al. ASCO 2009.

Bevacizumab + INF-α CALGB 90206 ASCO 2009

INF-α alone 3–5

8.4

Fro

m 2

00

5 u

ntil re

ce

ntly

Pazopanib ASCO 2009 Pazopanib 1.1

Improving OS in the 1st line treatment

of mRCC

1. Kane et al. Clin Cancer Res 2006;12:7271; 2. Hudes et al. N Eng J Med 2007;356:2271; 3. Escudier et al. N Engl J Med 2007;356:125; 4. Gore et al. ASCO 2008. Abstract 5039; 5. Escudier. ASCO 2008. Abstract 5025; 6. Rini et al. J Clin Oncol 2010;28:2137–2143;

7. Escudier et al. J Clin Oncol 2010; 28:2144–2150; 8. Figlin et al. ASCO 2008. Abstract 5024.

Fro

m 2

00

4 u

ntil re

ce

ntly

Best supportive care1

Temsirolimus2

IFN-α + IL-2 + 5-FU4,5

CALGB6

AVOREN7

Sunitinib8

Kane 2006

IFN

Figlin ASCO 2008

Gore ASCO 2008 IFN

Bevacizumab + IFN

Temsirolimus IFN

IFN

IFN Bevacizumab + IFN

Primary goal in the treatment of

mRCC: improving efficacy

Before targeted therapies the ORR was low (~2–13%), and median OS was 13.3 months

Effect of targeted therapies:

– In contrast to palliation we can count on long OS

– Comparing to cytokine based therapies PFS and OS significantly increased

1. Rini et al. J Clin Oncol 2008; 26:5422; 2. Escudier et al. Lancet 2007;370:2103; 3. Escudier. Cancer J 2008;14:325; 4. Escudier et al. N Engl J Med 2007;357:203;

5. Motzer et al. J Clin Oncol 2009; 27:3584; 6; Coppin et al. Cochrane Collaboration, 2006; 7. Motzer et al. N Engl J Med 2007;356:115; 8. Heng et al. Cancer 2009;115:776